Neutrophil extracellular trap-borne C3-driven endothelial dysfunction in <i>Klebsiella pneumoniae</i> liver abscess

<i>Klebsiella pneumoniae</i> (<i>K. pneumoniae</i>) liver abscess (KPLA) is a severe bacterial infection that is frequently complicated by intrahepatic thrombophlebitis and extrahepatic metastatic infections leading to high mortality rates. This study investigates the role of neutrophil extracellular traps (NETs) in endothelial injury and disease progression in KPLA. Our findings reveal that KPLA patients with intrahepatic thrombophlebitis are more prone to developing sepsis and extrahepatic migratory infections. <i>K. pneumoniae</i> induces NET formation via the TLR4-PI3Kα-AKT signaling pathway, and C3 deposition on NETs significantly contributes to endothelial injury. In a KPLA mouse model, increased C3 levels were observed in the liver, with NETs carrying substantial amounts of C3, disrupting the endothelial barrier and exacerbating liver injury. Treatment with the C3 inhibitor AMY-101 reduced C3 deposition on NETs, alleviated endothelial damage, significantly improved survival, and reduced extrahepatic dissemination, inflammatory infiltration, and lung injury while also suppressing systemic inflammation. Our findings underscore the pivotal role of C3 in NET-mediated endothelial damage and the pathogenesis of KPLA. Thus, targeting C3 deposition on NETs may be a promising therapeutic strategy to reduce endothelial injury, thrombosis, and extrahepatic infections in KPLA without compromising neutrophil antimicrobial function.